Dislipidemia The Lancet

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Seminar
Dyslipidaemia
Paul Durrington The lowering of serum cholesterol is increasingly recognised as essential in the prevention of coronary heart disease and other atherosclerotic disease. The success of statin trials and the need to deploy these drugs effectively in the population has led increasingly to the identification of many people whose serum cholesterol, triglycerides, and HDL-cholesterol require clinical assessment, and frequently treatment. Lipid disorders are mainly straightforward, but some are complex or resistant to simple treatment strategies. I have reviewed the clinical manifestations of disordered lipid metabolism (dyslipidaemia) and its management. The past 8 years have brought about a transformation in the clinical trial evidence for the effects of lowering serum cholesterol. Earlier scepticism was so great that proof was demanded that lipid lowering decreases not only mortality but also morbidity from coronary heart disease (CHD) and all-cause mortality1proof seldom required for other pharmacotherapies, except perhaps chemotherapy of malignant disease. Statin treatment now presents the greatest likelihood that a physician engaged in general medical practice can routinely prolong life.210 To translate clinical trial evidence into medical practice, many international and national recommendations have been developed that attempt to provide the clinician with simple algorithms to guide practice. However, not all patients have the simple lipid disorders the guidelines presuppose. Application of these approaches frequently reveals complex disorders. I have, therefore, surveyed current knowledge and practice across the whole field of dyslipidaemia. Adopting a clinical approach, I have grouped the disorders according to whether the biochemical phenotype is mainly hypercholesterolaemia, a combined increase in cholesterol and triglycerides, mainly hypertriglyceridaemia, hypolipidaemia, or secondary dyslipidaemia. control, hypertension clinics that dealt only with bloodpressure control, and cardiology and peripheral arterial disease clinics that specialised only in investigation and treatment of vascular consequences of atherosclerosis. Atherosclerosis is multifactorial, and lipid and other specialist clinics should form part of a cohesive preventive cardiovascular disease service that facilitates access to various specialties.
Hypercholesterolaemia
Familial hypercholesterolaemia The diagnosis of familial hypercholesterolaemia should always be sought among patients who have predominant hypercholesterolaemia, because it carries a particularly high risk of CHD that can easily be overlooked.1115 The existence of a dominantly inherited form of hypercholesterolaemia that causes tendon xanthomata was recognised for 50 years before the LDL receptor, and its diminished expression in familial hypercholesterolaemia was discovered in 1974.16 The gene for the LDL receptor is located on chromosome 19. The receptor allows cellular uptake of LDL from the tissue fluid. An outline of lipoprotein metabolism is shown in figure 1. Mutations of this receptor in familial hypercholesterolaemia prevent it from participating efficiently in LDL uptake because it cannot be transported to the cell surface, cannot bind properly to LDL once it gets there, cannot be internalised, or is not released from the endosome.11 Well before the discovery of the LDL-receptor defect in familial hypercholesterolaemia, the time LDL spent in the circulation before its catabolism was shown to be increased from the normal 25 days to about 45 days in heterozygotes, and even longer in homozygotes.17
Lipid clinics
With the inclusion of serum lipid measurements in screening programmes to identify individuals at high cardiovascular risk, unusual lipid disorders and clinicalmanagement issues have inevitably come to light (table). A need has arisen, therefore, for specialist clinicians, who are generally physicians or chemical pathologists who have trained in endocrinology (diabetes) and metabolism. Some lipid disorders present clinical difficulties that can be treated successfully only in a lipid clinic that provides specialised dietetic care, and laboratory (including genetics), nursing, and inpatient facilities. There is also a need for clinicians who can provide expertise in lipid disorders in primary care or district general hospitals. However, the mistakes of earlier single-risk-factor clinics should not be repeated, such as diabetes clinics that concentrated only on glycaemic
Lancet 2003; 362: 71731
University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK (Prof P Durrington FMedSci) (e-mail: pdurrington@man.ac.uk)
Search strategy
I drew early references, before 1980, largely from Havel RJ, Goldstein JL, Brown MS. Lipoproteins and lipid transport. In: Bondy PK, Rosenberg LE, eds. Metabolic control and disease, 8th edn. Philadelphia: WB Saunders, 1980: 393494. For later references, I searched the databases of Current Opinion in Lipidology, augmented by MEDLINE and PubMed, with the keywords: apolipoprotein, cholesterol, dyslipidaemia, hypercholesterolaemia, hyperlipidaemia, hyperlipoproteinaemia, hypertriglyceridaemia, lipoprotein, and triglyceride. I made my final selection dependent on limitations of space, whether the references quoted were a good source of further references, and on the basis of my own clinical, research, and teaching experience.
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For personal use. Only reproduce with permission from The Lancet
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Dyslipidaemia
WHO phenotype (hyperlipoproteinaemia) Type IIa: raised LDL
Diagnosis
Estimated prevalence among adults of European descent 2080% 02% 02%
Mainly hypercholesterolaemia*
Polygenic hypercholesterolaemia; familial hypercholesterolaemia; familial defective apolipoprotein B
Combined hypercholesterolaemia and hypertriglyceridaemia Triglycerides 20100 mmol/L
Type IIb: raised VLDL and LDL
Triglycerides 50200 mmol/L (cholesterol typically 70120 mmol/L) Triglycerides >100 mmol/L
Type III: raised chylomicron remnants and IDL Type V: raised chylomicrons and VLDL; or type I: raised chylomicrons Type IV None: low HDL
Familial combined if relatives have hyperlipoproteinaemia, otherwise simply combined hyperlipidaemia Frequently called type III hyperlipoproteinaemia, but also synonyms Familial lipoprotein lipase deficiency or heterozygous lipoprotein lipase mutation plus another cause for hypertriglyceridaemia Familial or sporadic hypertriglyceridaemia Most undiagnosed or associated with hypertriglyceridaemia. Occasionally heterozygous ABCAI mutation, APOAI mutation Familialeg, truncated apolipoprotein B
10%
002%
01%
Raised triglycerides alone Hypoalphalipoproteinaemia
1% 1025%
Hypobetalipoproteinaemia
None: low LDL and frequently VLDL
01001%
*Serum cholesterol >50 mmol/L. WHO phenotype has not been updated since views about what constitutes raised cholesterol have changed. When devised, 65 mmol/L would have been abnormal. Diagnoses can have distinct clinical phenotype. National Cholesterol Education Program recommendations III suggest triglycerides >15 mmol/L are unhealthy. Disorders occurring at frequencies of <001% have been omitted.
Primary dyslipidaemia that could present on measurement of serum cholesterol, HDL-cholesterol, and triglycerides
In open societies, such as the UK and USA, many mutations of the LDLR gene cause the clinical syndrome of familial hypercholesterolaemiamore than 700 mutations have already been reported.18 This genetic disorder is the most common in Europe and the USA, and affects about one in 500 people in its heterozygous form. In societies that have sprung from small numbers of early settlers or migrants, familial hypercholesterolaemia may be more common than in large open societies, and is caused by a smaller number of mutations (founder effect). Thus, for example, one in 80 South Africans of Dutch or French descent have familial hypercholesterolaemia, most of whom have one of only three different LDLR mutations.19 A similar situation seems to explain the high prevalence of familial hypercholesterolaemia in descendants of French Canadian trappers20 and in the Christian population of the Lebanon.21 Serum cholesterol concentrations in heterozygous familial hypercholesterolaemia are raised from birth. The normal mean serum cholesterol concentration in umbilical cord blood is only about 1720 mmol/L, and it is much higher in familial hypercholesterolaemia. However, screening by measurement of total serum cholesterol is not recommended among neonates because HDL-cholesterol, which is the dominant lipoprotein in fetal blood, can cause raised cholesterol concentrations more commonly than familial hypercholesterolaemia.22 Serum cholesterol rises in the first year of life to a mean of 41 mmol/L (95th percentile 52 mmol/L), which persists until the early teens, with mean concentrations being similar in boys and girls before puberty.22 The normal range for serum cholesterol varies little with age in childhood. A diagnostic threshold for childhood familial hypercholesterolaemia can, therefore, be defined and explains why total serum cholesterol higher than 67 mmol/L correctly identifies 95% of heterozygotes and only 25% of unaffected children.23 Cholesterol measurements must be confined to the children of affected parents to keep the chances of the disorder being discovered to one in two. If children in general were screened, the chance of finding a heterozygote is one in 500; therefore, even a 25% false-positive rate would falsely identify ten unaffected children for every affected one. In families of probands with familial hypercholes-
terolaemia, cholesterol concentrations as low as 55 mmol/L in children do not altogether exclude the diagnosis, particularly if the family is already on a cholesterol-lowering diet. Repeated measurements over time are required for these children. Serum cholesterol in people who have familial hypercholesterolaemia, as in the general population, increases with advancing age. Generally, in heterozygous familial hypercholesterolaemia values are about double what they would have been in the absence of the LDLAcquire apolipoproteins eg, E, CII ApoB48 TG Chylomicron TG Lipoprotein lipase TG Chylomicron remnant TG Can accept chylomicron remnants, VLDL, IDL, and LDL. Down-regulated when liver is cholesterol replete LRP LDL receptor Liver ApoAI SRBI HDL VLDL ApoB100 IDL TG LDL
TP CE
l e s t e r ol
Gut
ApoAI
Acquire apolipoproteins eg, E, CII Lipoprotein TG lipase TG Hepatic lipase TG . SRA O Small dense LDL Foam cell
LDL receptor NRM
Generalised cell
Figure 1: Outline of lipoprotein metabolism

CETP=cholesteryl ester transfer protein. IDL=intermediate-density lipoprotein. TG=triglyceride. LRP=LDL-receptor-like protein. SRA=scavenger receptor A. SRB1=scavenger receptor B1. NRM=non-receptor-mediated uptake. ABCA1=ATP binding cassette A1. O=oxygen free radical.
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Figure 2: Clinical manifestations of hyperlipidaemia

A: Achilles tendon xanthoma (heterozygous familial hypercholesterolaemia). B: Tendon xanthomata on dorsum of hand (heterozygous familial hypercholesterolaemia. C: Subperiosteal xanthomata (heterozygous familial hypercholesterolaemia). D: Planar xanthoma in antecubital fossa (homozygous familial hypercholesterolaemia). E: Striate palmar xanthomata (type III hyperlipoproteinaemia). F: Tuberoeruptive xanthomata on elbow and extensor surface of arm (type III hyperlipoproteinaemia). G: Milky plasma from patient with acute abdominal pain (severe hypertriglyceridaemia). H: Eruptive xanthomata on extensor surface of forearm (severe hypertriglyceridaemia).
receptor mutation.24 By adulthood, the serum cholesterol in heterozygous familial hypercholesterolaemia in the UK is thus typically in the range 90140 mmol/L. The diagnostic hallmarks of familial hypercholesterolaemia are tendon xanthomata.11,12 Other causes of these, cerebrotendinous xanthomatosis and phytosterolaemia are exceptionally rare. Xanthomata are localised infiltrates of lipid-containing foam cells that histologically resemble atheroma. Corneal arcus and xanthelasmata are not specific to familial hypercholesterolaemia, but they frequently occur much earlier in life in familial hypercholesterolaemia than in the more common polygenic type of hypercholesterolaemia. Nonetheless, many heterozygotes who have familial hypercholesterolaemia with obvious tendon xanthomata do not have
corneal arcus until much later in the disease course, and will never develop xanthelasmata.2527 Therefore, whether tendon xanthomata are present should be checked in all patients who have hypercholesterolaemia, irrespective of the presence of corneal arcus or xanthelasmata. The most common sites for tendon xanthomata are in the Achilles tendons and in the tendons overlying the knuckles (figure 2);12 less-common sites are in other tendons. Xanthomata are also commonly firmly attached to the tibial tuberosities at the site of insertion of the patellar tendon (subperiosteal xanthomata, figure 2). The skin overlying tendon xanthomata and subperiosteal xanthomata is a normal colour and does not appear yellow. The cholesterol accumulation is deep within the tendons and much of the swelling is fibrous. The
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xanthomata feel hard. Those in the Achilles tendons can become inflamed and many patients who have familial hypercholesterolaemia will, if asked, describe previous Achilles tenosynovitis. Xanthomata in the tendons on the dorsum of the hands are generally nodular or fusiform, and because they frequently overlie the knuckles (especially when the fist is clenched) and feel as hard as bone, physicians may miss them. The hands should be examined with the fingers extended when xanthomata are pulled back from the knuckles and can be moved from side to side. Achilles-tendon xanthomata may be visually obvious, because of thickening, swelling, irregularity, or nodularity of the tendon. They may, however, be subtle, the nodularity in the tendon becoming obvious only on palpation. The other frequent striking feature of familial hypercholesterolaemia is the adverse family history of CHD. If they remain untreated, more than half of male and about 15% of female heterozygotes die before age 60 years.14,28 Intriguingly, this high mortality associated with the inheritance of the LDLR mutation seems to have been absent in some families at least until the early part of the 20th century.29 This pattern generally parallels the rise of CHD mortality in North American and European Societies, although the risk to the familial hypercholesterolaemia heterozygote, particularly in early adulthood, compared with the average risk, is increased many-fold.15 In some present-day families, familial hypercholesterolaemia seems particularly devastating, causing CHD in men even in their 20s and in women before the menopause. In other families, male heterozygotes are unaffected until late middle age or sometimes older, and women survive to extreme old age with little evidence of CHD symptoms. The median age for the development of CHD in men is around 50 years. Typically, affected women in the same family develop CHD about 9 years later than their affected male relatives.30 There has been much speculation as to why some families with familial hypercholesterolaemia are more susceptible to CHD than others.26,3136 The nature of the mutation might itself be important, because some mutations will more severely compromise LDL uptake than others. The particular combination of mutations certainly affects the severity of homozygous familial hypercholesterolaemia, but this effect is less clear in heterozygous familial hypercholesterolaemia.32 Serum HDL-cholesterol relates to the likelihood of CHD in familial hypercholesterolaemia.33,34 Serum HDL cholesterol is generally lower than would be expected in familial hypercholesterolaemia, but in families in which this decrease is most obvious, prognosis is frequently bad. Generally, in familial hypercholesterolaemia, only serum cholesterol is raised. In a few patients, triglycerides are also raised, although seldom to more than 40 mmol/L, which has also been associated with a poor prognosis.33 Many such patients are obese, and obesity can increase their serum cholesterol, rarely even up to 200 mmol/L.12 Obesity is generally uncommon in familial hypercholesterolaemia, compared with almost all other hyperlipidaemias, in which obesity is over-represented. Hypertension and diabetes mellitus are also noticeably infrequent in familial hypercholesterolaemia.27 Therefore, familial hypercholesterolaemia may not be diagnosed if cholesterol screening is confined to patients with nonlipid risk factors. Serum lipoprotein (a) concentrations are raised in familial hypercholesterolaemia,36 and are related to increased CHD risk.37 Increased intestinal cholesterol absorption related to co-inheritance of an apolipoprotein E 4 genotype may also worsen prognosis.33
CHD is by far the most common manifestation of atheroma in heterozygous familial hypercholesterolaemia. In homozygous familial hypercholesterolaemia particularly, but also occasionally in heterozygotes, atheromatous deposits may be present in the root of the aorta and can extend into the aortic valve cusps.36,39 This form of supravalvar aortic stenosis can cause sudden death in severely affected heterozygotes and in homozygotes. Some patients also develop carotid and cerebrovascular atheroma, although less commonly than CHD. Femoropopliteal atheroma is uncommon and is really encountered only in cigarette smokers who have familial hypercholesterolaemia. The discovery of a new case of familial hypercholesterolaemia provides the opportunity to detect affected relatives. Such an approach, known as cascade family screening, is better than general or selective screening, and should be introduced, involving trained nurses working from regional lipid clinics to ensure family members receive adequate treatment and access to medical services.13,27,40 The Simon Broome register definition of heterozygous familial hypercholesterolaemia provides a good guideline for identification of affected relatives:15 serum cholesterol concentrations higher than 67 mmol/L in children younger than 16 years or more than 75 mmol/L in adults, plus tendon xanthomata in the patient or first-degree or second-degree relatives. Whether the familial hypercholesterolaemia genotype can be present in people without the clinical syndrome and whether, therefore, genetic testing could be useful is debated.13 The high numbers of mutations involved, however, mean no simple widely applicable means of genetic testing is likely to be generally feasible in the UK and USA. Some encouraging results have been reported in South Africa and in the Netherlands, where fewer mutations account for a higher proportion of familial hypercholesterolaemia.41 Although the controversy over genetic testing continues, many people with obvious clinical features of familial hypercholesterolaemia who are at risk of premature CHD go undetected or the importance of the diagnosis and the rigour with which this disorder must be treated is not appreciated.13 The statin drugs have been a major advance in the management of familial hypercholesterolaemia in adults.42,43 Most familial hypercholesterolaemia heterozygotes can achieve serum cholesterol concentrations lower than 70 mmol/L, and some even lower than 50 mmol/L. The most potent of the statins may be required at maximum dose to lower the highest cholesterol concentrations. Occasionally the response to statins alone is inadequate, and addition of a bile-acid-sequestrating agent is the most logical approach. The development of more potent statins or use of the cholesterol-absorption inhibitor, ezetimibe may supersede this approach. Nicotinic acid in doses up to 7 g daily is also effective in lowering cholesterol, but must be carefully monitored and is rarely acceptable to patients because of the severe flushing it invariably produces. Partial ileal bypass is frequently successful in lowering serum cholesterol,44 but has been used less since the advent of statins. The penetrance of familial hypercholesterolaemia judged in terms of CHD risk generally breeds true in families.30 This information can be helpful in making decisions about the age at which to introduce statin treatment. Generally, despite the need for more evidence about the safety of statins in childhood,45 in male heterozygotes statin treatment should be started in the late teens, but could be started earlier if the family history is particularly adverse. In many women the introduction of cholesterol-lowering medication can safely be left until
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later, but there are reproductive issues. Women should be advised against pregnancy while they are taking statins since the risks are unknown. Many women do not, however, contemplate motherhood until their 30s or early 40s by which time they should have started statin therapy. In planned pregnancies women can discontinue medication while they are attempting to conceive and during pregnancy. The time to start statin treatment must, therefore, be negotiated with each female patient, but generally women choose to begin statin treatment in their early 20s because they know they will stop for around a year per planned pregnancy, dependent on how long conception takes. I believe there is no justification for use of bile-acid sequestrants in children, even if these drugs are judged safe.46 This treatment is poorly tolerated by children and, thus, adherence is inadequate; therefore, these drugs serve no function in preventing vascular disease. The poor tolerance can also alienate children from the clinic, which means they can be lost altogether during the rebellious years of adolescence when effective treatment with statins should be considered. For the same reasons, repeated blood testing in children should be avoided between diagnosis and the time when statin intervention is being considered. Children should generally receive no treatment other than a healthy diet, exercise, and avoidance of smoking. The introduction of lipid-lowering treatment is not the only reason for identifying heterozygotes for familial hypercholesterolaemia. The disorder is still not widely recognised. Therefore, when patients present with manifestations of CHD they are frequently inappropriately managed. Many physicians do not believe that such young apparently fit people can have severe CHD, which commonly leads to delay in investigations, especially coronary angiography. Certainly, exercise electrocardiography should be done promptly if any symptom even slightly suggestive of CHD occurs, and patients who have familial hypercholesterolaemia should be encouraged to report such symptoms. Coronary angiography should be done since it frequently reveals surprisingly extensive disease, despite non-severe symptoms. Measurement of the pressure gradient across the aortic valve with echocardiography should also be undertaken if a systolic murmur is present. Homozygous familial hypercholesterolaemia rarely occurs by chance. The odds of two unrelated heterozygotes marrying is one in 250 000, and the chances of them having a child who is homozygous is one in four, meaning that the theoretical incidence of homozygous familial hypercholesterolaemia is one in 1 million. The chances of a marriage between heterozygotes is increased greatly when there is, for example, a tradition of firstcousin marriage. In such circumstances both the LDLR mutations in homozygotes are likely to be the same. These people are thus true homozygotes (strictly compound homozygotes), as opposed to homozygotes that arise from random unions, in which LDLR mutations are probably different for each allele. Serum cholesterol concentrations in homozygous familial hypercholesterolaemia are almost invariably higher than 150 mmol/L and can be as high as 300 mmol/L.11,12 Xanthomata develop in childhood. In addition to florid tendon xanthomata, orange-yellow cutaneous planar xanthomata develop, particularly in the popliteal and antecubital fossae (figure 2), buttocks, and in the webs between the fingers. They can also develop on the palms of the hands and front of the knees. Polyarthralgia is common and supravalvar aortic stenosis can cause sudden death. Many homozygotes develop
angina of effort in childhood due to the aortic stenosis and coronary atheroma. Myocardial infarction has been recorded as early as age 2 years, and life expectancy does not generally extend beyond the early 20s. Although homozygous familial hypercholesterolaemia is always serious, the worst prognosis seems to occur when both LDLR mutations are of the type that completely prevent LDL receptors appearing on the cell surface.11 The most potent statins can lower serum cholesterol by up to 30% in homozygous familial hypercholesterolaemia, and ezetimibe can produce a further 20% decrease.47 However, even then substantial hypercholesterolaemia will remain. Plasmapheresis or LDL apheresis is the best approach to treatment.48,49 Generally the procedure must be done every 2 weeks. Liver transplantation has also met with some success.50 Normal donor hepatic LDL receptors are introduced; the liver is the site of about half of LDL catabolism in normal people. The LDLR gene can be transfected into LDLR knockout mice, in which it is expressed and lowers serum cholesterol, albeit briefly, before it is cleared from the cell nuclei along with viral DNA.51 As soon as a vector that allows foreign DNA to persist safely in mammalian cells become available, homozygous familial hypercholesterolaemia will probably be one of the first genetic disorders to be treated by this technique. Other defects in LDL catabolism in familial hypercholesterolaemia syndrome The familial hypercholesterolaemia phenotype is generally caused by an LDLR mutation. Rarely, however, the same syndrome is caused because apolipoprotein B, the component of LDL that allows it to bind to the LDL receptor, has a mutation that interferes with binding. Thus, a similar defect in LDL catabolism is produced, called familial defective apolipoprotein B. This disorder is most commonly due to an aminoacid substitution at position 3500 in the aminoacid sequence of apolipoprotein B.52 This mutation has a frequency of about one in 600 in the general population, although usually it does not produce a particularly severe hyperlipidaemia. However, as many as 4% of people with clinical familial hyercholesterolaemia may have familial defective apolipoprotein B.53 These patients hypercholesterolaemia seems to respond more easily to treatment than is generally the case in familial hypercholesterolaemia. Currently, about half the patients in the UK and USA who have a clinical diagnosis of heterozygous familial hypercholesterolaemia will have identifiable mutations of the LDLR gene.54 Genetic techniques might be failing to detect LDLR mutations in some of these patients. However, another gene or genes involved in LDL catabolism might be discovered, which, when they undergo mutation, will explain the presence of familial hypercholesterolaemia in some patients. A type of familial hypercholesterolaemia that is inherited as an autosomal recessive has been reported to be due to mutations of a gene involved in the internalisation of the LDL and LDLreceptor complex from the cell surface by endocytosis.55 The mutation produces a clinical phenotype intermediate between heterozygous and homozygous familial hypercholesterolaemia, and has so far been described mainly, but not exclusively, in people from Sardinia.55,56 Polygenic hypercholesterolaemia The most common cause of raised LDL cholesterol is not an inherited catabolic defect but a hepatic overproduction of VLDL, which is converted to LDL sufficiently rapidly that VLDL triglyceride concentrations remain within
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normal limits but LDL cholesterol rises.57 The main causes are high fat intake, particularly saturated fat, and obesity. Genetic factors are also assumed to be important, because individuals vary in their cholesterol response to diet. However, there is no clear pattern of inheritance; a combination of more than one genetic variant is generally required for this type of hypercholesterolaemia (polygenic inheritance). Hypercholesterolaemia is prevalent in Europe and the USA and countries that have adopted features of their cultures,58,59 particularly lifestyle, values, and so on. Treatment has proved troublesome. There is no shortage of good evidence that lowering cholesterol decreases CHD risk,210,60 but difficulty lies in the translation of this approach into clinical and public-health practice. Countries with high CHD mortality are those in which the typical cholesterol concentration of their inhabitants is much higher than that in countries where lower CHD risk is the rule.58,59 Within apparently healthy populations there is an exponential relation between serum cholesterol and coronary risk.61 The slope of this relation is greater among younger than older people. In middle-age, the risk increases by about 2% for each 1% increase in cholesterol. Even in countries such as China, where the average cholesterol concentration is less than 40 mmol/L, this gradient of risk is still evident, although set at a lower level than, for example, in the UK, where the average cholesterol in middle age is around 60 mmol/L.62 The great difficulty for clinicians has been to comprehend that in a society in which cholesterol concentrations and coronary risk are generally high, CHD events occur most frequently among people whose serum cholesterol is average, and that even at low concentrations, cholesterol can contribute to high CHD risk. Most heart attacks will occur in people whose cholesterol and CHD risk are average simply because they are more numerous than those with higher degrees of risk.63 Thus, the expectation that the typical individual who has a myocardial infarction will also have substantially higher-than-average cholesterol is wrong. For too long opportunities to prevent CHD or recurrent CHD have been missed because practitioners in societies in which risk factors for CHD are prevalent have sought to treat only patients with exceptionally high cholesterol concentrations. In the UK, for example, the typical patient with acute myocardial infarction will have a cholesterol concentration of around 60 mmol/L, the average for the middle-aged and older population. There is excellent evidence that lowering cholesterol irrespective of its initial concentration will lessen the likelihood of a recurrence.26 Of course, it is perfectly reasonable to ask why some people will have a heart attack with low cholesterol concentrations but others will not. This issue poses the greatest difficulty in primary prevention if we are not to treat huge numbers of people, many of whom will be treated needlessly. Identification of people who have high susceptibility to CHD is easy if they already have some manifestation of CHD or other atherosclerotic disease. The relation between serum cholesterol (or HDL-cholesterol) and CHD risk is steeper in myocardial infarction survivors than in the general population,64 and in half of people who die from CHD the disease has been previously symptomatic,65 frequently early enough for preventive measures to have been effective.26 Ideally we should be able to identify people most susceptible to cholesterol even before symptoms develop (primary prevention) and treat them. In practice we can identify some of these people by taking into account risk factors other than serum cholesterol,6568 such as sex,
HDL-cholesterol concentration, blood pressure, smoking, diabetes, and family history. The Framingham risk equation has found favour in the identification of individuals more likely to benefit from statin treatment.6772 However, this high-risk approach will not prevent most heart attacks, which will occur at an average concentration of serum cholesterol and in the presence of average CHD risk. Currently, the only hope of preventing such typical events is to reduce the levels of risk factors in the population as a whole. To achieve this reduction would require a concerted public-health policy aimed at reducing smoking, improving nutrition, and encouraging exercise. Cholesterol reduction has a special place in CHD prevention because, in societies in which the typical concentrations are low, such as those in Asia, other CHD risk factors, such as smoking, hypertension, and diabetes seem to have much less impact on CHD risk than in societies with high cholesterol concentrations.58,73,74 This effect is consistent with our concepts of atherogenesis, in which LDL is intimately involved, and the other risk factors operate by increasing its atherogenicity by modifying its chemical and physical structure or by facilitating its passage into the arterial wall.75 Furthermore, the reasons for the substantial differences in CHD risk between different societies have been consistently attributed to nutritional differences: countries with the highest energy consumption, particularly in the form of saturated fats as opposed to carbohydrate, have the highest CHD rates.58 Obesity and high consumption of saturated fats both raise serum cholesterol.76,77 Sadly, as people migrate from Asian societies and consume the diet more typical of countries with high CHD rates, their CHD risk increases.78,79 Similarly, as the diet in Asian countries becomes increasingly more like European and US diets, they are poised to experience an epidemic of CHD. This epidemic will be worse than in other countries because Asian countries are so highly populated and the financial resources to deal with it are limited. In addition, metabolic polymorphisms present in Asian populations that may have survival potential on a subsistence-level diet with low fat content, might, if a high-fat diet is adopted, lead to higher rates of dyslipidaemia, glucose intolerance, and CHD than in people of European descent.80 High-risk patients will derive little individual benefit from public-health policy; a higher proportion of them will benefit from lipid-lowering drug therapy. Treatment should be directed not so much at cholesterol concentrations, but at high CHD risk. Certainly, among patients with clinical CHD or equivalent risk, serum cholesterol concentrations as low as 40 mmol/L should be treated.36 Evidence is strongest for statins. Dietary intervention should not, however, be abandoned, but realistically it frequently does not achieve an adequate reduction in serum cholesterol outside the metabolic ward.81 This inadequate effect may be related to commercial and cultural pressures or to more complex issues of early nutritional effects, perhaps as early as in utero,82 which produce metabolic resistance in later life. There have been nine major randomised statin trials with clinical endpoints (figure 3).28,60,83 The trials were done in patients with a wide range of CHD risk, from around 5%2 to less than 1% for each year of study.8 The results show decreases in CHD and stroke risk of about a third, irrespective of cholesterol concentration at entry, at least down to 35 mmol/L among men and women for primary and secondary prevention.5,8,9 The trials show that the improvement in risk with statins is maintained in old age, despite the relative decrease in the predictive power
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45
GREACE
Decrease in LDL cholesterol (%)
40 35 30
PROSPER HPS CARE WOSCOPS LIPID AFCAPS/TexCAPS 4S
25 20
ALLHAT
15 0 0 10 20 30 40 50 Decrease in CHD risk (%) 60 70
Figure 3: Decrease in combined CHD morbidity and mortality as a function of average LDL-cholesterol reduction in randomised clinical trials of statin treatment
Endpoint in AFCAPS/TexCAPS was fatal and non-fatal myocardial infarction, otherwise it was death from CHD or non-fatal myocardial infarction. Bars show 95% CI.
of cholesterol with advancing age in epidemiological studies.84 The decrease in CHD risk with statin therapy was evident by the second year of such trials and there is some suggestion that a decrease in cardiovascular risk can be achieved in the 6 months immediately after an acute coronary event.85 The starting of statin treatment at that time seems to have no adverse effects,86,87 and it is one way of ensuring that statin treatment is not subsequently overlooked and its long-term benefit denied. Whether cholesterol needs to be measured at all is questioned in making the decision to introduce statin treatment in patients with CHD or other atherosclerosis. Measurement might be best avoided if it impedes the introduction of statin treatment. As for the dose, an evidence-based dose could be prescribed and left at that, but measurement of serum cholesterol after the introduction of a statin is essential to monitor its effect and to titrate the dose to achieve an LDL-cholesterol target. The statin trials are unfortunately confounded as to what should be the LDL-cholesterol target of statin treatment. None was designed to establish what the target should be. Post-hoc analysis comparing patients with greater and lesser degrees of cholesterol lowering breaks the randomisation and involves factors other than the dose and efficacy of the statin. One trial did aim to compare the effect of achieving the US National Cholesterol Education Program LDL-cholesterol target of 25 mmol/L with normal care among patients with CHD.6 95% of the active intervention group, who received 1080 mg atorvastatin daily (average 24 mg), achieved the LDL-cholesterol target, compared with only 3% receiving normal care. The LDL-cholesterol in the active intervention group was 41% lower than in the normal care group, which resulted in a decrease in fatal and non-fatal new myocardial infarction of 51% and in overall mortality of 43% during the 3 years of the trial. The decrease in LDL cholesterol and in CHD risk achieved was greater than in any previous statin trial. Whether an absolute LDL-cholesterol concentration should be the only target of statin treatment or whether the starting concentration should also be taken into
account remains unsettled. Although this consideration complicates recommendations, it is potentially important. The trials do seem to show that the percentage decrease in cholesterol produces a similar percentage decrease in relative CHD risk, irrespective of the initial LDL cholesterol concentrationa 1% decrease in LDL cholesterol produces roughly a 125% decrease in CHD risk (figure 3). Thus in a patient who has an LDLcholesterol concentration of 60 mmol/L, a 40% decrease in LDL cholesterol will produce a concentration of 36 mmol/Lhigher than the absolute target of less than 25 mmol/L, but nevertheless a 50% decrease in CHD risk. In another patient whose LDL cholesterol is only 30 mmol/L initially, a reduction in LDL to 24 mmol/L, achieving the absolute target, will result from a 20% decrease in LDL cholesterol, but represents only a 25% decrease in CHD risk. This patient may have a similar initial CHD risk to that of the first patient because his susceptibility to cholesterol is increased say by the presence of other risk factors. Thus, despite achieving a lower LDL target the second patient will have a poorer prognosis, unless an LDL target that is lower still were achieved. Therefore, for a given reduction in CHD risk, the absolute target can differ between patients. The issue is further complicated because some trials suggest that the decrease in CHD risk is not linearly related to the percentage decrease in LDL cholesterol, but declines exponentially with no detectable additional benefit beyond, for example, a decrease of 25%.88 If, however, the overall results of the statin trials are considered in relation to the average LDL-cholesterol reductions they achieved, there does seem to be increased benefit from greater reduction in LDL cholesterol, although the CI are wide (figure 3). This analysis, however, has the advantage that the randomisation within the individual trials is not disturbed. On the other hand an additional complication is that different statins were used in the trials. Thus, some statins might be more antiatherogenic than others. Currently, therefore, to aim for at least a 30% decrease in LDL cholesterol or an absolute concentration of 25 mmol/L, whichever is lower, seems reasonable.
Combined hypercholesterolaemia and hypertriglyceridaemia

Familial combined hyperlipidaemia Hypertriglyceridaemia associated with hypercholesterolaemia is most commonly due to a combined increase in LDL and VLDL. Combined hyperlipidaemia is a common disorder, occurring in around 30% of myocardial-infarction survivors, and may affect as many as one in 50 of the general population.89,90 The disorders pattern is frequently familial, and is commonly referred to as familial combined hyperlipidaemia. In family studies, phenotype has proved variable, and some family members may have an isolated rise in cholesterol or triglycerides, whereas in others rises are combined. Originally, combined hyperlipidaemia was suggested to have a dominant monogenic mode of inheritance.89 Now it is thought to result from genetic factors, some predisposing to high cholesterol and some to hypertriglyceridaemia running in the same family.91 Thus variants in exons or promoters of the lipoprotein lipase gene or its activators and inhibitors, apolipoprotein CII and CIII, or of the cholesteryl ester transfer protein (CETP) gene or the genes regulating uptake or release of non-esterified fatty acid by adipose tissue, such as acylation stimulating protein or insulin resistance, may, in some families, be co-inherited with a polygenic tendency for high hepatic
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14 12 Myocardial infarction risk 10 8 6 4 2 0 0
Serum cholesterol (mmol/L) 90 75 60
small dense LDL concentrations.106,107 Interest has been shown in the development of more specific inhibitors of cholesteryl ester transfer protein.108 The relation of low HDL concentrations with CHD risk is the subject of much interest and is undoubtedly complex. Low HDL concentrations are potentially associated with heightened activity of cholesteryl ester transfer protein and small dense LDL. Attention has also been drawn to the capacity of HDL to protect LDL against atherogenic oxidative modification, which seems to reside in the enzyme paraoxonase located on HDL.109 Small dense LDL and hyperapobetalipoproteinaemia Patients with and without diabetes who have high triglyceride concentrations may, despite apparently normal serum or LDL cholesterol, have high serum concentrations of apolipoprotein B, the main protein component of LDL.110 Sniderman and colleagues111 were the first to realise the cause was the presence of a cholesterol-depleted LDL, and termed the disorder hyperapobetalipoproteinaemia. Direct measurements of the cholesterol-depleted LDL subtype, known as LDLIII or small dense LDL, in epidemiological studies have shown a strong association with the risk of developing CHD,101 and experimental studies show it to be more susceptible to oxidation than more buoyant LDL.98,112,113 Small dense LDL concentrations increase as serum triglycerides concentrations rise to higher than 15 mmol/L.100,114 Small dense LDL is generally also associated with low HDL-cholesterol concentrations, but raised concentrations of serum cholesterol or LDL cholesterol are not necessary for it to be present. Methods for the direct measurement of small dense LDL are not currently available in clinical practice, but its presence undoubtedly explains many of the cases of acute myocardial infarction occurring in people with low cholesterol concentrations. More patients with small dense LDL would be detected, if serum apolipoprotein B was measured instead of serum cholesterol.115 There is a strong case for at least monitoring statin treatment in terms of apolipoprotein B rather than cholesterol reduction, because concentrations of apolipoprotein B frequently relate more closely to subsequent CHD event rates.115,116 Type III hyperlipoproteinaemia Type III hyperlipoproteinaemia (synonyms: broad disease, floating disease, dysbetalipoproteinaemia, remnant removal disease) results from the presence in the circulation of large amounts of chylomicron remnants and intermediate-density lipoprotein (or partly metabolised VLDL), commonly collectively termed VLDL. This disorder is rare and cannot be described in detail here, but reviews of the disorder are available.12,117,118 Serum cholesterol and triglyceride concentrations are raised (table). Striate palmar and tuberoeruptive xanthomata occur (figure 2). If untreated, the likelihood of CHD and peripheral arterial disease increase strikingly. The disorder generally responds to weight reduction and fibrate treatment. In the absence of typical xanthomata, type III cannot be distinguished on simple lipid measurement from type IIb or V hyperlipoproteinaemia. DNA testing can be used to identify apolipoprotein E 2 homozygosity present in 90% of cases. If this test is undertaken, it may show that a patient is unlikely to have type III hyperlipoproteinaemia, but provide the unwelcome finding that apolipoprotein E 4 is present. This apolipoprotein has been linked with Alzheimers disease, certainly in its late-onset form and, in
2 3 4 5 6 Serum triglycerides (mmol/L)
Figure 4: Fatal and non-fatal myocardial infarction risk over next 6 years per 100 men
Risk calculated from reference 95, by use of Spirit 6 calculator for men aged 50 years with no family history of CHD, non-smokers and non-diabetic, and with systolic blood pressure 140 mm Hg and serum HDL cholesterol 14 mmol/L. Plotted as function of serum triglyceride concentration at three different serum cholesterol concentrations.
VLDL secretion, and thus high concentrations of its product, LDL. Raised serum triglyceride concentrations are associated with low HDL partly because they may be the result of diminished lipoprotein lipase activity, which not only catabolises triglycerides in the core of triglyceride-rich lipoproteins, but in doing so generates HDL components from their surface. An increased flux of cholesteryl ester from HDL to triglyceride-rich lipoproteins in hypertriglyceridaemia causes a further tendency to low HDL-cholesterol concentrations.92 This process is mediated by cholesteryl ester transfer protein.93 Hypertriglyceridaemia increases the risk of atherosclerosis to higher than that which would be predicted from the cholesterol concentration (figure 4).94104 The raised CHD risk seems to stem partly from the low HDL-cholesterol concentrations and partly from an increased concentration of cholesterol-depleted LDL (small dense LDL), the presence of which is not necessarily appreciated from the serum or LDL cholesterol concentration, and which is highly atherogenic.100 The effectiveness of statins to reduce cardiovascular risk210 means that these drugs should be the first-line treatment for familial combined hyperlipidaemia. Their triglyceride-lowering effect, which is mainly through an increase in the hepatic reuptake of VLDL, intermediatedensity lipoprotein, and LDL105 is, however, generally less than that of fibrate drugs, which increase lipoprotein lipase activity by a mechanism involving peroxisome proliferator activator receptors and .106 Their cholesterol-lowering effect is, however, smaller than that of statins and is due mainly to a decrease in VLDL cholesterol. -3 fatty acids also lower VLDL triglyceride with little effect on serum cholesterol. Fibrates or -3 fatty acids may thus be combined with statins to lower triglycerides further, but the former combination increases the risk of myositis, albeit probably rarely. Nicotinic acid, although it can lower cholesterol and triglycerides, almost invariably causes unpleasant flushing in therapeutic doses.12 There is evidence that all four classes of drugs decrease activity of cholesteryl ester transfer protein and
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some studies, with the early-onset type. Laboratories should probably report only whether apolipoprotein E 2 homozygosity is present or absent to avoid information being openly available in medical records without patients consent.119 If the diagnosis of type III hyperlipoproteinaemia is deemed still possible when apolipoprotein E 2 homozygosity is absent, plasma should be sent to a centre that can provide ultracentrifugation to identify the presence of VLDL typical of type III.117 Paraproteinaemia, which can produce hyperlipoproteinaemia that can mimic type III, should be excluded.12
Predominant hypertriglyceridaemia
Moderate hypertriglyceridaemia Patients who have raised fasting triglycerides, whose serum cholesterol is not raised, have dwindled in numbers over the years as high serum cholesterol cut-off values have been revised downwards from 65 to 50 mmol/L. Thus, many people formerly deemed to have hypertriglyceridaemia alone have now become classified as having combined hyperlipidaemia. Currently, the most common reason to encounter hypertriglyceridaemia in the presence of cholesterol concentrations lower than 50 mmol/L is in patients with combined hyperlipidaemia receiving statin treatment who have some persisting hypertriglyceridaemia. An LDL cholesterol target is inappropriate in such patients because much of their serum cholesterol will be in VLDL. The National Cholesterol Education Program Adult Treatment Panel III recommendations, partly for this reason, provide a non-HDL-cholesterol threshold for the introduction of statin treatment and a non-HDL-cholesterol target.72 Non-HDL cholesterol is the difference between the serum cholesterol and the HDL cholesterol, and generally represents the sum of LDL and VLDL cholesterol. Although not measured routinely, many patients with increased triglycerides and apparently low LDL cholesterol actually have increased concentrations of small dense LDL.96100 Serum apolipoprotein B, if available, thus gives a better indication of the concentration of atherogenic lipoproteins than does nonHDL cholesterol.115 No trial evidence shows that treating moderate hypertriglyceridaemia is of benefit in primary prevention unless cholesterol is also raised. In the three secondary-prevention trials of fibrate drugs, a significant decrease in CHD events occurred in only one, all-cause mortality was reduced in none, and initial serum triglyceride concentration determined the likelihood of benefit in only one.120122 On the other hand, -3 fatty acids do decrease all-cause mortality, albeit by an antidysrhythmic mechanism that may not involve triglycerides,123 and in larger doses can decrease triglycerides by almost as much as fibrates.124 Severe hypertriglyceridaemia When fasting triglyceride concentrations higher than 10 mmol/L are encountered, almost invariably chylomicrons and VLDL are contributing to the hypertriglyceridaemia.125 Chylomicronaemia can produce spectacularly high concentrations of serum triglycerides, sometimes exceeding 100 mmol/L. Under these circumstances, because chylomicrons contain cholesterol from the diet and through synthesis in the gut, and because VLDL, which also contains cholesterol is also raised, the accompanying serum cholesterol concentration may also be increased sometimes by 30 mmol/L or more with no increase in LDL cholesterol. In severe hypertriglyceridaemia, chylomicrons and VLDL are typically increased, because both compete for
the same clearance mechanism (lipoprotein lipase). The lipoprotein phenotype is thus normally type V. This severe hypertriglyceridaemia generally ensues when an increase in hepatic VLDL production, either familial or secondary to, for example, obesity, diabetes, alcohol, or oestrogen administration, is associated with decreased lipolysis of VLDL and chylomicrons, which again may be genetic or acquired, such as in hypothyroidism, blockade, or diabetes mellitus (diabetes can cause overproduction of VLDL and decreased lipoprotein lipase activity). Since the clearance mechanism is already overloaded with VLDL, the rise in serum triglyceride concentrations when chylomicrons enter the circulation after a fatty meal may be tumultuous and they may spend days rather than hours in the circulation.12,125 The serum takes on the appearance of milk (figure 2). Overall the frequency of severe hypertriglyceridaemia (>100 mmol/L) is probably no more than one in 1000 in adults. The disorder is more common among people with type 2 diabetes. Rarely, severe hypertriglyceridaemia is caused by familial lipoprotein lipase deficiency, a genetic deficiency in lipoprotein lipase activity. This disorder is inherited as an autosomal recessive trait. Generally it is due to mutations in the lipoprotein lipase gene, leading to defective function or production,125 but occasionally it is due to a genetic deficiency of apolipoprotein CII, the activator of lipoprotein lipase.126 In familial lipoprotein lipase deficiency, severe hypertriglyceridaemia may be encountered in childhood. Occasionally, in children and young adults presenting for the first time, type I hyperlipoproteinaemia arises, in which only serum chylomicron concentrations are raised. VLDL is not raised probably because hepatic lipase can catabolise the lower concentrations of VLDL produced in childhood, although it is unable to compensate for the absence of lipoprotein lipase in chylomicron catabolism. With advancing age VLDL rises to concentrations higher than those that can be cleared by hepatic lipase. VLDL along with chylomicrons thus accumulate in the circulation and type V hyperlipoproteinaemia becomes the rule.127 Eruptive xanthomata are characteristic of extreme hypertriglyceridaemia. These appear as yellow papules on the extensor surfaces of the arms and legs, buttocks, and back (figure 2). Hepatosplenomegaly frequently occurs. Liver imaging shows the liver to be fatty, and bonemarrow biopsy may reveal macrophages engorged with lipid droplets (foam cells).128 Because the triglyceride-rich lipoproteins can interfere with the measurement of transaminases, giving spuriously high values, liver disease, especially alcoholic liver disease, may be difficult to exclude other than by the prompt resolution of the syndrome when a low-fat diet is started. Another feature is lipaemia retinalis (pallor of the optic fundus, in which the retinal veins and arteries appear white). The risk of atheroma in familial lipoprotein lipase deficiency is uncertain,125 but it does complicate severe hypertriglyceridaemia, in which there is some lipoprotein lipase activity, albeit diminished. Precise estimation of the risk from this hyperlipidaemia per se is difficult because it is so frequently associated with insulin resistance or frank diabetes, which are themselves risk factors for atherosclerosis. If these disorders are included as part of the syndrome, coronary heart disease and peripheral arterial disease are common. The reason why the complete absence of lipoprotein lipase obscures the risk of atheroma is unclear. It may be because the incidence of diabetes is not raised in familial lipoprotein lipase deficiency or because fibrinogen and factor VII activity are not increased,129 or because the conversion of VLDL and
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chylomicrons to the atherogenic IDL, LDL, and remnant lipoproteins is impaired in the absence of lipoprotein lipase. Serum LDL and apolipoprotein B concentrations are frequently normal or low.110 Acute pancreatitis may occur when serum triglyceride concentrations become higher than 2030 mmol/L.12 Falsely low serum amylase activities can be encountered because of interference by triglyceride-rich lipoproteins in the laboratory method. All laboratories should inspect serum for milkiness (figure 2) before reporting normal or only moderately raised serum amylase activity among patients who have severe abdominal pain to prevent clinicians from wrongly excluding acute pancreatitis. Generally the pain subsides within a few hours or days of starting nasogastric aspiration and intravenous fluids, with nothing taken by mouth. Pseudohyponatraemia in extreme hypertriglyceridaemia may lead to serious consequences, if it is interpreted as true hyponatraemia. When the serum triglycerides exceed 4050 mmol/L the concentration of sodium in the aqueous phase, and thus the serum osmolality, may be normal. However, spurious serum sodium concentrations of 120130 mmol/L are reported because much of the volume of the serum sample in which sodium is measured is occupied by lipoproteins as opposed to water. The treatment of severe hypertriglyceridaemia can be difficult. Secondary causes should be excluded. The correct diet is low in all types of fat (to shut off the supply of chylomicrons), frequently to as little as 20 g per day. If adhered to, the correct diet is more effective than pharmacotherapy. Fibrate drugs generally have some effect. Of the other drugs available, I have not been impressed by fish oil, which contributes to chylomicrons, although the more refined -3 fatty acid preparation that has become available may prove more effective. Mediumchain triglycerides make matters worse, despite claims to the contrary, because preparations available contain quantities of long-chain fatty acids and the medium-chain triglycerides themselves contribute to hepatic VLDL synthesis even though they arrive in the portal blood and bypass chylomicron formation. Bile-acid-sequestrating
agents also exacerbate hypertriglyceridaemia. Anecdotally, when I have been unable to lower triglycerides sufficiently to prevent recurrent acute pancreatitis, I have been impressed by the effect of high-dose antioxidant therapy in preventing attacks, even though this treatment does not lower triglycerides further.130
Secondary hyperlipidaemia
Secondary hyperlipoproteinaemias are those caused by another primary disorder that has hyperlipidaemia as a complication (panel). In societies in which polygenic hyperlipoproteinaemia is prevalent, secondary hyperlipoproteinaemia will have high impact. For example, in the UK and USA, CHD is the most common cause of premature death in diabetes mellitus, but in Japan it is only rarely a complication.73,131 Despite the variety of secondary disorders, space permits only diabetes mellitus to be reviewed. Diabetes mellitus The dominant hyperlipidaemia in diabetes is hypertriglyceridaemia,12,132 which is most likely to be associated with hypercholesterolaemia and with decreased HDL cholesterol in type 2 diabetes.133 The hypertriglyceridaemia is associated not simply with an increase in VLDL, but also in intermediate-density lipoprotein and small dense LDL.134,135 Since neither of these lipoproteins contribute greatly to a rise in lipid concentrations, the term dyslipoproteinaemia is particularly aptly applied in diabetes. There is also an increased activity of cholesteryl ester transfer protein.136,137 Additionally, plasma fibrinogen concentration, which is increased in type 1 and 2 diabetes, relates to serum
50 40 30 20 Percentage rise per quintile High cholesterol High blood pressure High triglyceride High glucose Low HDL cholesterol
Common causes of secondary hyperlipoproteinaemia

Endocrine Diabetes mellitus Hypothyroidism Pregnancy Nutritional Obesity Alcohol excess Renal Nephrotic disease Chronic renal failure Hepatic disease Cholestasis Heptocellular dysfunction Immunoglobulin excess Paraproteinaemia Gout Association, rather than a cause Drugs -adrenoreceptor blockers Thiazide diuretics Steroid hormones Microsomal enzyme-inducing agents Retinoic-acid derivatives Protease inhibitors (HIV infection)
10 0 0 1 2 3 4 Quintiles of body-mass index 5
50 40 30 20 10 0 0 1 2 3 4 Quintiles of serum insulin 5
Figure 5: Effect of increasing body-mass index and serum insulin on prevalence of high blood pressure, hypercholesterolaemia, hypertriglyceridaemia, and high glucose in men
Data from the British Regional Heart Study (reference 143).
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triglyceride concentrations.138 Lipoprotein abnormalities in type 1 diabetes may be less frequent than in type 2, but the risk of coronary heart disease in type 1 diabetes is more frequently compounded by the presence of proteinuria. In type 1 diabetes that is uncomplicated by proteinuria, the risk of coronary heart disease is about two to three times that of non-diabetic people of a similar age. Proteinuria increases the risk as much as 40-fold,139 which may stem partly from hypertension and an exacerbation of the dyslipoproteinaemia that accompany the development of proteinuria.140,141 However, the increase in risk is greater than can be explained in this way and may result because the proteinuria reflects a generalised increase in the permeability of arterial endothelium, promoting the entry of macromolecules into the subintima and thus accelerating atherogenesis.142 The increased blood glucose concentration in diabetes mellitus results from insulin resistance, insulin deficiency, or both. Insulin resistance may be present in non-diabetic, generally obese, people who are still able to secrete sufficient insulin to maintain control of blood sugar, but in such people there is often hypertriglyceridaemia with low HDL cholesterol and hypercholesterolaemia, hypertension (figure 5)143 and increased risk of coronary heart disease. This syndrome is commonly referred to as the insulin resistance syndrome (syndrome X) or metabolic syndrome.72,144 Clearly, the disorder has features in common with familial combined hyperlipidaemia and with diabetes. Indeed, a substantial proportion of people who have this syndrome ultimately develop diabetes,145 although sometimes not until after they have already developed CHD,146 which explains partly why glycaemic control in diabetes seems to have little impact in preventing its atheromatous complications.133 Statin treatment, on the other hand, is effective in preventing CHD in diabetes5,6,133 and may lessen the excess case fatality in diabetes associated with acute myocardial infarction.147 In one report, statin treatment postponed the development of diabetes.148 Women who have diabetes, particularly those with type 2 disease, generally have a distribution of adipose tissue resembling that of obese men around the abdomen and waist, rather than the more female pattern, which involves the buttocks and thighs but leaves the waist relatively small. The protection from CHD that most women have, even those with familial hypercholesterolaemia, is largely lost by those who have diabetes, which it is suggested results from this androgenisation.149 Many women with a similar body shape, but who have not yet developed diabetes, are insulin resistant, hypertensive, have hyperlipidaemia, and have an increased risk of CHD. There is an undoubted overlap here too with polycystic ovary syndrome.150
Some people who have serum cholesterol concentrations around 1035 mmol/L will have heterozygous familial hypobetalipoproteinaemia, an autosomal dominant disorder in which truncated apolipoprotein B mutations have been described.152 This hypolipidaemia is benign. However, the much rarer homozygous hypobetalipoproteinaemia and abetalipoproteinaemia (inherited as autosomal recessive), which produce more severe hypocholesterolaemia, are associated with retinitis pigmentosa, steatorrhoea, fatty liver, abnormally shaped erythrocytes (acanthocytes), and a syndrome that resembles Friedreichs ataxia, and is preventable with fat-soluble vitamin administration. Mutation of the microsomal triglyceride transfer protein (MTP) gene necessary for VLDL assembly rather than of the APOB gene is associated with apobetalipoproteinaemia. Analphalipoproteinaemia (Tangier disease) is a very rare disorder with virtually absent HDL because of rapid clearance, and reduced LDL cholesteryl ester, but increased tissue cholesteryl ester deposition throughout the body. This deposition leads to enlarged orange-yellow tonsils and adenoids, lymph-node enlargement, hepatosplenomegaly, bone-marrow infiltration (thrombocytopenia), orange-brown spots on the rectal mucosa, neuropathy, and corneal cloudiness.153 The disorder has been ascribed to mutation of the ABCA1 gene encoding the cholesterol efflux regulatory protein.154 Low HDL-cholesterol (hypoalphalipoproteinaemia) has been defined as concentrations lower than 10 mmol/L. This definition would make it a common disorder, affecting as many as 25% of adults in the USA.155 Only rarely could it be caused by a single-gene disorder, such as heterozygous APOAI or ABCA1 mutation. More frequently it is the result of similar factors to those leading to hypertriglyceridaemia, and is associated with obesity and the metabolic syndrome or frank diabetes (figure 5). Low HDL cholesterol is a common finding in patients who have CHD, and frequently precedes this disease by many years.156 Measurement of HDL cholesterol is, therefore, essential in CHD risk prediction.157 However, low HDL-cholesterol concentrations cannot be effectively raised by pharmacological means or lifestyle changes of raising.72 A 20% increase in HDL cholesterol would be more than could be expected in most patients, but with an initial concentration of, for example, 09 mmol/L, even this improvement would be hardly appreciable in the clinic. Therefore, particular attention to achieving LDLcholesterol or non-HDL-cholesterol targets in patients with low HDL cholesterol is recommended,72 which in higher-risk patients will generally require statin treatment. Further research is required to find out whether more precise diagnosis of the causes of low HDL-cholesterol can identify people at particular CHD risk and allow the development of more specific interventions.
Conflict of interest statement
None declared.
Hypolipidaemia
Hypolipidaemia is an increasing clinical problem, since more cases are being discovered because of population screening for high cholesterol. People who have had a low serum cholesterol concentration all their lives seem to be at no disadvantage unless the decrease is substantial, as in abetalipoproteinaemia. Indeed, their freedom from cardiovascular disease may lead to longevity. When the disorder is discovered for the first time it is frequently difficult to know whether the low cholesterol is due to an acquired disease, such as malignant disease (eg, colonic or prostatic neoplasms, leukaemia, reticulosis, or myeloma) or malabsorption (eg, due to a short bowel, blind-loop syndrome, coeliac disease, pancreatic exocrine insufficiency, or giardiasis).12,151
Acknowledgment
I thank C Price for the preparation of this manuscript.
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Uses of error
Errors: Incompetence, ineptitude or failure
Lionel H Opie Errors are of most interest if they reflect overt incompetence or ineptitude (my first example) or failure to do what should have been done (my second example). In about 1973, I was doing a student teaching ward round certain that I knew most of internal medicine and all of cardiology. During a teaching ward round the patient, an elderly gentleman of about 76 years of age with a cerebrovascular accident thought to be on the basis of atrial fibrillation, developed another stroke, the direct result of my ward round. Why? I wanted to explain to the students that carotid sinus massage was no therapy for atrial fibrillation, though an excellent selfhelp remedy in younger patients with supraventricular tachycardia. By way of demonstration, totally unnecessary for the health of the patient, I proceeded to massage the right carotid sinus, and within seconds he went pale. I was totally surprised and did not know what to do. There were no resuscitation trolleys on the ward. Instead of thumping or pumping the chest, I just stood there, paralysed. I slowly came to realise that he had had carotid sinus syncope that precipitated another stroke. Why this happened is still not clear. On the background of increased carotid sinus sensitivity of the elderly, increased conduction block probably induced severe bradycardia with reduced cerebral blood flow. Great care is needed to protect the patients interests during teaching ward rounds. My other major error occurred only a few weeks before writing this piece. In a meta-analysis of calcium channel blockers (CCBs), my co-worker and I found that CCB therapy for hypertension reduced stroke but increased myocardial infarction, while leaving cardiovascular and total mortality unchanged relative to conventional therapy by diuretics or blockers. In view of the continuing controversy about the safety of CCBs, it was my hope that this article and the other recent meta-analyses published, would help settle the issue. But, to cut a long story short, we made a calculation error in the rate of reduction of non-fatal stroke, which we claimed was the very high rate of 25%. We incorrectly emphasised stroke reduction as being statistically more robust than increased non-fatal myocardial infarction. In fact, stroke reduction just about exactly balanced myocardial infarct increase. Although the overall results are still intact, any error in this contentious area is serious. Published errors are very difficult to correct. What should we have done to avoid the error? Simple addition of the numbers for non-fatal stroke would have shown up the error. Ironically, there have been other addition errors in previous metaanalyses that I had picked up and criticised. So I should have been ultra careful. Thus, before publication, apply commonsense checks to statistics. It is not the job of the referees to pick up statistical errors.
Hatter Institute, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa (L H Opie MD)
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THE LANCET Vol 362 August 30, 2003 www.thelancet.com

WHO phenotype (hyperlipoproteinaemia) Type IIa: raised LDL

Estimated prevalence among adults of European descent 2080% 02% 02%

Polygenic hypercholesterolaemia; familial hypercholesterolaemia; familial defective apolipoprotein B

Combined hypercholesterolaemia and hypertriglyceridaemia Triglycerides 20100 mmol/L

Type IIb: raised VLDL and LDL

Raised triglycerides alone Hypoalphalipoproteinaemia

None: low LDL and frequently VLDL

LDL receptor NRM

Figure 1: Outline of lipoprotein metabolism

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

Figure 2: Clinical manifestations of hyperlipidaemia

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

Decrease in LDL cholesterol (%)

15 0 0 10 20 30 40 50 Decrease in CHD risk (%) 60 70

Combined hypercholesterolaemia and hypertriglyceridaemia

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

14 12 Myocardial infarction risk 10 8 6 4 2 0 0

Serum cholesterol (mmol/L) 90 75 60

2 3 4 5 6 Serum triglycerides (mmol/L)

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THE LANCET Vol 362 August 30, 2003 www.thelancet.com

Common causes of secondary hyperlipoproteinaemia

10 0 0 1 2 3 4 Quintiles of body-mass index 5

50 40 30 20 10 0 0 1 2 3 4 Quintiles of serum insulin 5

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THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

THE LANCET Vol 362 August 30, 2003 www.thelancet.com

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